Competing memories of mitogen and p53 signalling control cell-cycle entry.
Competing memories of mitogen and p53 signalling control cell-cycle entry.
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DOI：
10.1038/nature23880
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发表时间：
2017-09-21
期刊：
影响因子：
64.8
通讯作者：
Meyer T
中科院分区：
文献类型：
--
作者：
Yang HW;Chung M;Kudo T;Meyer T
细胞增殖的调节对于免疫反应、组织修复和维持器官功能以维持人类健康是必要的。当增殖细胞完成有丝分裂时，一小部分新生的子细胞立即进入下一个细胞周期，而同一群体中的其余细胞则进入短暂或持续的静止状态。两种细胞周期途径之间的这种选择是否是由于有丝分裂原信号传导的自然变异或其他潜在原因所致尚不清楚。在这里，我们证明人类细胞根据可变丝裂原和应激信号的竞争记忆做出这种基本的细胞周期进入或退出决定。母细胞不会在有丝分裂前清除细胞周期检查点的信号传导历史，而是将 DNA 损伤诱导的 p53 蛋白和有丝分裂原诱导的细胞周期蛋白 D1 (CCND1) mRNA 传递给新生的子细胞。有丝分裂后，转移的 CCND1 mRNA 和 p53 蛋白诱导细胞周期蛋白 D1 和 CDK 抑制剂 p21 的可变表达，这几乎完全决定子细胞中的细胞周期定型。我们发现 p21 对细胞周期蛋白 D1-CDK4 活性的化学计量抑制以超灵敏的方式控制视网膜母细胞瘤 (Rb) 和 E2F 转录程序。因此，子细胞通过将可变丝裂原和应激信号的记忆转化为细胞周期蛋白 D1 和 p21 表达之间的竞争来控制增殖-静止决策。我们提出了一种基于自然变异、记忆和竞争的细胞周期控制原理，可最大限度地提高生长细胞群的健康状况。
Regulation of cell proliferation is necessary for immune responses, tissue repair, and upkeep of organ function to maintain human health. When proliferating cells complete mitosis, a fraction of newly born daughter cells immediately enter the next cell cycle, while the remaining cells in the same population exit to a transient or persistent quiescent state. Whether this choice between two cell-cycle pathways is due to natural variability in mitogen signalling or other underlying causes is unknown. Here we show that human cells make this fundamental cell-cycle entry or exit decision based on competing memories of variable mitogen and stress signals. Rather than erasing their signalling history at cell-cycle checkpoints before mitosis, mother cells transmit DNA damage-induced p53 protein and mitogen-induced cyclin D1 (CCND1) mRNA to newly born daughter cells. After mitosis, the transferred CCND1 mRNA and p53 protein induce variable expression of cyclin D1 and the CDK inhibitor p21 that almost exclusively determines cell-cycle commitment in daughter cells. We find that stoichiometric inhibition of cyclin D1-CDK4 activity by p21 controls the retinoblastoma (Rb) and E2F transcription program in an ultrasensitive manner. Thus, daughter cells control the proliferation-quiescence decision by converting the memories of variable mitogen and stress signals into a competition between cyclin D1 and p21 expression. We propose a cell-cycle control principle based on natural variation, memory and competition that maximizes the health of growing cell populations.
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影响因子：
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